Endogenous and Exogenous Opioids in Pain

Annual Review of Neuroscience, Journal Year: 2018, Volume and Issue: 41(1), P. 453 - 473

Published: May 31, 2018

Opioids are the most commonly used and effective analgesic treatments for severe pain, but they have recently come under scrutiny owing to epidemic levels of abuse overdose. These compounds act on endogenous opioid system, which comprises four G protein-coupled receptors (mu, delta, kappa, nociceptin) major peptide families (β-endorphin, enkephalins, dynorphins, nociceptin/orphanin FQ). In this review, we first describe functional organization pharmacology system. We then summarize current knowledge signaling mechanisms by opioids regulate neuronal function neurotransmission. Finally, discuss loci action along peripheral central pain pathways, emphasizing pain-relieving properties against affective dimension experience.

Language: Английский

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Opioid-induced hyperalgesia: Cellular and molecular mechanisms

Neuroscience, Journal Year: 2016, Volume and Issue: 338, P. 160 - 182

Published: June 24, 2016

Language: Английский

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Opioid receptors: drivers to addiction?

Nature reviews. Neuroscience, Journal Year: 2018, Volume and Issue: 19(8), P. 499 - 514

Published: June 22, 2018

Language: Английский

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Opioid-Induced Tolerance and Hyperalgesia

CNS Drugs, Journal Year: 2019, Volume and Issue: 33(10), P. 943 - 955

Published: Oct. 1, 2019

Language: Английский

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Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development

Pharmacological Reviews, Journal Year: 2020, Volume and Issue: 73(1), P. 163 - 201

Published: Dec. 14, 2020

Compulsive drug seeking that is associated with addiction hypothesized to follow a heuristic framework involves three stages (binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation) domains of dysfunction (incentive salience/pathologic habits, negative emotional states, executive function, respectively) via changes in the basal ganglia, extended amygdala/habenula, frontal cortex, respectively. This review focuses on neurochemical/neurocircuitry dysregulations contribute hyperkatifeia, defined as greater intensity emotional/motivational signs symptoms during withdrawal from drugs abuse affect stage cycle. Hyperkatifeia provides an additional source motivation for compulsive reinforcement. Negative reinforcement reflects increase probability response remove aversive stimulus or hyperkatifeia augmented by genetic/epigenetic vulnerability, environmental trauma, psychiatric comorbidity. Neurobiological targets involve neurocircuitry amygdala its connections within-system neuroadaptations dopamine, enkephalin/endorphin opioid peptide, γ-aminobutyric acid/glutamate systems between-system prostress corticotropin-releasing factor, norepinephrine, glucocorticoid, dynorphin, hypocretin, neuroimmune antistress neuropeptide Y, nociceptin, endocannabinoid, oxytocin systems. Such are mediate hedonic set point gradually gains allostatic load shifts homeostatic state state. Based preclinical studies translational date, medications behavioral therapies reset brain stress, antistress, pain return them homeostasis would be promising new medication development.

Significance Statement

The focus this cycle driving force addiction. Medications reverse resetting returning

Language: Английский

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A Motivational and Neuropeptidergic Hub: Anatomical and Functional Diversity within the Nucleus Accumbens Shell

Neuron, Journal Year: 2019, Volume and Issue: 102(3), P. 529 - 552

Published: May 1, 2019

Language: Английский

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Advances in Achieving Opioid Analgesia Without Side Effects

Frontiers in Pharmacology, Journal Year: 2018, Volume and Issue: 9

Published: Nov. 29, 2018

Opioids are the most effective drugs for treatment of severe pain, but they also cause addiction and overdose deaths, which have led to a worldwide opioid crisis. Therefore, development safer opioids is urgently needed. In this article, we provide critical overview emerging opioid-based strategies aimed at pain relief improved side effect profiles. These approaches comprise biased agonism, targeting (i) receptors in peripheral inflamed tissue (by reducing agonist access brain, use nanocarriers, or low pH-sensitive agonists); (ii) heteromers multiple monovalent, bivalent, multifunctional ligands); (iii) receptor splice variants; (iv) endogenous peptides preventing their degradation enhancing production by gene transfer). Substantial advancements underscored pharmaceutical new such as κ-receptor agonists, treatments augmenting action opioids, entered clinical trials. Additionally, there several promising novel comprehensively examined preclinical studies, might require careful rethinking.

Language: Английский

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Five Decades of Research on Opioid Peptides: Current Knowledge and Unanswered Questions

Molecular Pharmacology, Journal Year: 2020, Volume and Issue: 98(2), P. 96 - 108

Published: June 2, 2020

In the mid-1970s, an intense race to identify endogenous substances that activated same receptors as opiates resulted in identification of first opioid peptides. Since then, >20 peptides with receptor activity have been discovered, all which are generated from three precursors, proenkephalin, prodynorphin, and proopiomelanocortin, by sequential proteolytic processing prohormone convertases carboxypeptidase E. Each these binds types (μ, δ, or κ), albeit differing affinities. Peptides derived proenkephalin prodynorphin broadly distributed brain, mRNA encoding precursors highly expressed some peripheral tissues. Various approaches used explore functions specific behaviors brain circuits. These methods include directly administering ex vivo (i.e., excised tissue) (in animals), using antagonists infer peptide activity, genetic knockout precursors. Collectively, studies add our current understanding function opioids, especially when similar results found different approaches. We briefly review history peptides, highlight major findings, address several myths widely accepted but not supported recent data, discuss unanswered questions future directions for research.

SIGNIFICANCE STATEMENT

Activation synthetic drugs leads central biological effects, including analgesia respiratory depression, may be primary Instead, play complex overlapping roles a variety systems, reward pathways, important direction research is delineation role individual

Language: Английский

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A bifunctional nociceptin and mu opioid receptor agonist is analgesic without opioid side effects in nonhuman primates

Science Translational Medicine, Journal Year: 2018, Volume and Issue: 10(456)

Published: Aug. 29, 2018

The small-molecule AT-121 is an agonist of nociceptin and mu opioid peptide receptors mediates analgesia without opioid-associated side effects in nonhuman primates.

Language: Английский

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A Paranigral VTA Nociceptin Circuit that Constrains Motivation for Reward

Cell, Journal Year: 2019, Volume and Issue: 178(3), P. 653 - 671.e19

Published: July 1, 2019

Language: Английский

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